Microneedles and methods of manufacture thereof

Abstract

A microneedle array is provided for administrating a drug or other substance into a biological tissue. The array includes a base substrate; a primary funnel portion extending from one side of the base substrate; and two or more solid microneedles extending from the primary funnel portion, wherein the two or more microneedles comprise the substance of interest. Methods for making an array of microneedles are also provided. The method may include providing a non-porous and gas-permeable mold having a two or more cavities each of which defines a microneedle; filling the cavities with a fluid material which includes a substance of interest and a liquid vehicle; drying the fluid material to remove at least a portion of the liquid vehicle and form a plurality of microneedles that include the substance of interest, wherein the filling is conducted with a pressure differential applied between opposed surfaces of the mold.

We claim: 
     
       1. A method for making a microneedle array, the method comprising:
 (a) providing a mold having an upper surface and an opening in the upper surface, wherein the opening leads to a first cavity proximal to the upper surface and to a plurality of second cavities below the first cavity, wherein the first cavity defines a primary funnel portion, and wherein the second cavities define an array of microneedles; 
 (b) loading into the second cavities a first material which comprises a substance of interest dissolved or suspended in a first liquid vehicle; 
 (c) drying the first material in the mold to remove at least a portion of the first liquid vehicle to form at least a tip portion of a microneedle in each of the second cavities, wherein the tip portion comprises the substance of interest; 
 (d) loading the first cavity and a proximal portion of the second cavities unoccupied following steps (b) and (c) with a second material which comprises a matrix material dissolved or suspended in a second liquid vehicle; 
 (e) drying the second material in the mold to remove at least a portion of the second liquid vehicle to form (i) a primary funnel portion, and (ii) proximal portions of the microneedles, wherein the primary funnel portion comprises the matrix material, 
 wherein the formed tip portions and proximal portions of the microneedles together with the formed primary funnel portion are the microneedle array, and 
 wherein at least step (b) comprises spinning the mold in a centrifuge to create a gravitational force to drive the first material into the second cavities. 
 
     
     
       2. The method of  claim 1 , further comprising removing the microneedle array from the mold. 
     
     
       3. The method of  claim 1 , wherein the mold further defines, for each of the microneedles, a secondary funnel portion between the first cavity and the second cavities. 
     
     
       4. The method of  claim 3 , wherein the secondary funnel portions each comprise a straight, tapered sidewall. 
     
     
       5. The method of  claim 1 , wherein the loading of step (b) and/or step (d) comprises direct deposition of droplets of the first and/or second materials, respectively, to the mold. 
     
     
       6. The method of  claim 5 , wherein the droplets have a width that is larger than a width of a funnel-mold interface. 
     
     
       7. The method of  claim 1 , wherein the drying of step (c) and/or step (e) is conducted under centrifugation. 
     
     
       8. The method of  claim 1 , wherein the substance of interest comprises an active pharmaceutical ingredient. 
     
     
       9. The method of  claim 1 , wherein the first material further comprises a matrix material. 
     
     
       10. The method of  claim 9 , wherein the matrix material of the first material is a water-soluble matrix material. 
     
     
       11. The method of  claim 10 , wherein the water-soluble matrix material comprises polyvinyl alcohol, dextran, carboxymethylcellulose, maltodextrin, a sugar, or a combination thereof. 
     
     
       12. The method of  claim 9 , wherein the matrix material of the first material comprises a biodegradable polymer. 
     
     
       13. The method of  claim 1 , wherein the second material does not comprise the substance of interest. 
     
     
       14. The method of  claim 1 , wherein the microneedles of the microneedle array are conical. 
     
     
       15. A method for making a microneedle array, the method comprising:
 (a) providing a mold having an upper surface and an opening in the upper surface, wherein the opening leads to a first cavity proximal to the upper surface and to a plurality of second cavities below the first cavity, wherein the first cavity defines a primary funnel portion, and wherein the second cavities define an array of microneedles; 
 (b) loading into the second cavities a first material which comprises a substance of interest dissolved or suspended in a first liquid vehicle; 
 (c) drying the first material in the mold to remove at least a portion of the first liquid vehicle to form at least a tip portion of a microneedle in each of the second cavities, wherein the tip portion comprises the substance of interest; 
 (d) loading the first cavity and a proximal portion of the second cavities unoccupied following steps (b) and (c) with a second material which comprises a matrix material dissolved or suspended in a second liquid vehicle; 
 (e) drying the second material in the mold to remove at least a portion of the second liquid vehicle to form (i) a primary funnel portion, and (ii) proximal portions of the microneedles, wherein the primary funnel portion comprises the matrix material, 
 wherein the formed tip portions and proximal portions of the microneedles together with the formed primary funnel portion are the microneedle array, and 
 wherein the second cavities defining the microneedles are closed at their tips and the mold is subjected to centrifugation to drive the first material into the second cavities and remove air therefrom. 
 
     
     
       16. The method of  claim 15 , further comprising removing the microneedle array from the mold. 
     
     
       17. The method of  claim 15 , wherein:
 the mold further defines, for each of the microneedles, a secondary funnel portion between the first cavity and the second cavities, and 
 the mold is subjected to centrifugation to drive the second material into the second cavities and/or the space defining the secondary funnel portions, and remove air therefrom. 
 
     
     
       18. The method of  claim 15 , wherein the drying of step (c) and/or step (e) is conducted under centrifugation. 
     
     
       19. A method for making microneedles, the method comprising:
 (a) providing a mold having an upper surface, an opposed lower surface, and an opening in the upper surface, wherein the opening leads to a first cavity proximal to the upper surface and to a second cavity below the first cavity defining at least one microneedle; 
 (b) partially loading into the second cavity, via the opening in the mold, with a first material which comprises a substance of interest dissolved or suspended therein; 
 (c) solidifying the first material in the mold to form a tip portion of the at least one microneedle in the cavity, wherein the tip portion comprises the substance of interest; 
 (d) loading the first cavity and a proximal portion of the second cavity unoccupied following steps (b) and (c), via the opening in the mold, with a second material; 
 (e) solidifying the second material in the mold to form respective remaining portions of the at least one microneedle; and 
 (f) removing the at least one microneedle from the mold, 
 wherein at least part of one or more of steps (b)-(e) is conducted under centrifugation. 
 
     
     
       20. The method of  claim 19 , wherein the first material and/or second material comprises a melt. 
     
     
       21. The method of  claim 20 , wherein the solidifying in step (c) and/or step (e) comprises cooling the melt. 
     
     
       22. The method of  claim 19 , wherein the solidifying in step (c) and/or step (e) comprises cooling the first material and/or second material, respectively. 
     
     
       23. The method of  claim 19 , wherein the solidifying in step (c) comprises drying the first material. 
     
     
       24. The method of  claim 23 , wherein the drying comprises freeze drying. 
     
     
       25. The method of  claim 19 , wherein the solidifying in step (c) comprises curing the first material. 
     
     
       26. The method of  claim 25 , wherein the curing comprises heating the first material. 
     
     
       27. The method of  claim 25 , wherein the curing comprises cooling the first material. 
     
     
       28. The method of  claim 25 , wherein the curing comprises exposing the first material to light. 
     
     
       29. The method of  claim 28 , wherein the light is ultraviolet light. 
     
     
       30. The method of  claim 19 , wherein the solidifying in step (e) comprises drying the second material. 
     
     
       31. The method of  claim 30 , wherein the drying comprises freeze drying. 
     
     
       32. The method of  claim 19 , wherein the solidifying in step (e) comprises curing the second material. 
     
     
       33. The method of  claim 32 , wherein the curing comprises heating the second material. 
     
     
       34. The method of  claim 32 , wherein the curing comprises cooling the second material. 
     
     
       35. The method of  claim 32 , wherein the curing comprises exposing the second material to light. 
     
     
       36. The method of  claim 35 , wherein the light is ultraviolet light. 
     
     
       37. The method of  claim 19 , wherein the loading of the first or second cavities comprises overfilling the first or second cavities with the first or second material, respectively. 
     
     
       38. The method of  claim 19 , wherein the loading of the first or second cavities comprises partially filling the first or second cavities with the first or second material, respectively. 
     
     
       39. The method of  claim 19 , wherein the loading of the first or second cavities comprises completely filling the first or second cavities with the first or second material, respectively.